Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets.

Journal article

Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects. The most important reaction for this class of steroids is the reversible C11 keto/beta-hydroxyl conversion between receptor-binding 11beta-OH steroids and the nonbinding 11-oxo compounds, carried out by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). In this study, we determined the role of glucocorticoid conversion by 11beta-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11beta-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11beta-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of beta-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11beta-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11beta-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cell-specific manner plays a major role in glucocorticoid physiology in rodents and man.

Authors: Davani, B; Khan, A; Hult, M; Mårtensson, E; Okret, S

• Journal: Journal of biological chemistry
• Volume: 275
• Issue: 45
• Pages: 34841-34844
• Publication date: 2000-11-01
• DOI: 10.1074/jbc.c000600200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Dose-Response Relationship, Drug; Animals; Glucose; Mice, Mutant Strains; Reverse Transcriptase Polymerase Chain Reaction; Carbenoxolone; Transcription, Genetic; Ligands; Mice; Genes, Reporter; Hydroxysteroid Dehydrogenases; Isoenzymes; Insulin; Humans; Diabetes Mellitus, Type 2; Tissue Distribution; RNA, Messenger; Kinetics; Pancreas; Corticosterone; 11-beta-Hydroxysteroid Dehydrogenases; Islets of Langerhans; Anti-Ulcer Agents; Mice, Knockout; Glucocorticoids